Researchers from the Clinical Institute of Pathology at MediUni Vienna have discovered a new cause for the kidney disease, FSGS. About half of FSGS cases can be explained by genetic causes or a circulatory factor in the blood, but until now, scientists have been unable to uncover the cause for the remaining 50% of cases. The MediUni Vienna researchers, in collaboration with an international team, have traced the kidney damage that occurs in FSGS to over-expression of a micro-RNA, miR-193a, in glomerular cells. This over-expression turns off gene regulation in the cells, leading to damage of the kidney filtration barrier.

The discovery uncovers a valuable new target for treating FSGS. In future studies, the scientists hope to discover the reasons behind the over-expression of miR-193a and ways they might prevent it.

Source:

Faulty Gene Regulation Triggers the Kidney Disease FSGS, Medical Xpress, March 20, 2013

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Researchers at Stanford School of Medicine have discovered that the podocyte cells that make up the kidney filter membrane may be able to regenerate during normal kidney function. Scientists have long believed that these cells, which suffer damage in more than 90 percent of chronic kidney diseases, such as FSGS and diabetic nephropathy, could not renew themselves. Researcher Steven Artandi, M.D., Ph.D., said, “It used to be thought that you were born with podocytes, and died with the same podocytes—you don’t make any more during your lifetime.”

In this study, Artandi and fellow scientists found that the over-expression of TERT, a protein component of the enzyme telomerase, causes podocytes to de-differentiate and divide, and the glomeruli to collapse as a result. A similar scenario occurs in patients with HIV-associated nephropathy or HIVAN. Interestingly, examination of the glomeruli of HIVAN patients revealed increased expression of TERT. Experiments in lab mice showed that increasing the expression of TERT produced the same result as in humans; once over-expression ceased, the cells stopped dividing and began acting like specialized podocyte cells again. The researchers also found that the Wnt signaling pathway is activated in patients with HIVAN. Wnt proteins are important to embryonic development and cell differentiation. The scientists were able to block Wnt signaling in mice with HIVAN to stop podocyte division and improve function. They now hope to discover if podocyte regeneration occurs during healthy kidney function. Dr. Artandi said, “If we can harness this regeneration, we may one day be able to treat people with chronic kidney disease.”

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Regeneration of Specialized Cells Offers Hope for Treating Chronic Kidney Disease, Researchers Say, Stanford School of Medicine, December 4, 2011

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Researchers at University of Miami Miller School of Medicine and Harvard Medical School have discovered an important molecular mechanism behind worsening kidney disease. In a disease such as FSGS, for example, the kidney filter membrane (also known as the slit diaphragm) is damaged, allowing proteins to leak into the urine. The initial damage causes further injury to the podocyte cells, which make up the filter membrane. The podocytes die, resulting in more proteinuria and scarring of the kidneys.  The researchers found that when filter membrane injury occurs, CD2AP—a protein important for podocyte survival and proper signaling in the filter membrane—splits and releases the protein dendrin. This increases activity of protease cathepsin L, or Catl, which then degrades CD2AP, continuing the cycle of damage.

The study’s senior author, Jochen Reiser, M.D., Ph.D., explained, ““We knew that proteinuria is a risk for more and progressive renal disease, but now we understand a mechanism for how this is occurring. A healthy filter membrane regulates a healthy transcriptional program—both of which are altered in disease. The idea to improve not only proteinuria by rebuilding the slit diaphragm of podocytes, but also improve podocyte survival opens novel concepts for nephroprotection in otherwise progressive renal diseases, such as FSGS.”

Sources:

Nephrologists Discover Key to Kidney Disease Progression, University of Miami Miller School of Medicine, September 12, 2011

CD2AP in Mouse and Human Podocytes Controls a Proteolytic Program That Regulates Cytoskeletal Structure and Cellular Survival, JCI, The Journal of Clinical Investigation, October 3, 2011

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A team of nephrologists and researchers at University of Miami Miller School of Medicine have discovered a factor in the blood that may be responsible for up to two-thirds of the cases of focal segmental glomerulosclerosis or FSGS. They found that an excess of serum soluble urokinase receptor (suPAR) activates a protein in the kidney podocytes called ß3 integrin. The podocytes, which serve as a filtration barrier, begin to move and allow protein to pass into the urine. The process leads to breakdown and fusing of the podocytes, impaired filtration, and glomerular scarring. The scientists found that many patients with FSGS have elevated levels of suPAR in the blood. Therapies to reduce suPAR levels or stop the suPAR-ß3 interaction could one day prove beneficial. Tests for suPAR levels in the blood could also identify patients at risk of developing recurring FSGS after kidney transplantation.

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Nephrologists Discover Cause of Common Kidney Disease, University of Miami Miller School of Medicine, July 31, 2011

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Kidney podocytes (shown in yellow) wrapping around the capillaries of the glomerulus

Researchers at University of Miami Miller School of Medicine, collaborating with a team of doctors and surgeons, have uncovered how the drug Rituximab, normally used to treat non-Hodgkin’s lymphoma, rheumatoid arthritis, and chronic lymphocytic leukemia, also works to prevent FSGS from recurring in children and young adults with kidney transplants. The drug appears to bind to and preserve a protein (SMPDL-3b) on kidney podocytes. The protein is under-expressed in patients with recurring FSGS. Rituximab stabilizes protein expression, protecting the fiber formation and structure of the podocytes and preserving their filtering ability. One dose of the drug appears to improve kidney function for up to 12 months.

This could greatly impact the 80% of FSGS patients who experience a recurrence of the disease after kidney transplantation. The discovery may help scientists predict which patients are at risk of a recurrence and provides them with vital clues for understanding the cause and development of FSGS at the molecular level.

Source:

Physicians Discover How Cancer Drug Works to Help Prevent Recurrent Kidney Disease, University of Miami, Miller School of Medicine, June 1, 2011

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